The role of incretin-based therapies and SGLT2 inhibitors as adjuncts to insulin therapy in type 2

diabetes with special reference to IDegLira Running head: Adjuncts to insulin therapy in T2DM

with special reference to IDegLira

Authors:

JPH Wilding1 and SC Bain2

Affiliations:

1. Department of Obesity and Endocrinology, University of Liverpool, UK

2. Institute of Life Science, Swansea University, Swansea, UK

Corresponding author:

Prof John PH Wilding, Department of Obesity and Endocrinology Institute of Ageing & Chronic

Disease, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool, L9 7AL

United Kingdom

Email: J.P.H.Wilding@liverpool.ac.uk; Tel: +44(0)151 529 5899 Fax: +44(0)151 529 5888

Word count: 4,774 (limit 5,000 words); Abstract: 249

References: 65

Funding source: Novo Nordisk

Conflicts of interest disclosures: JW has consulted and/or received lecture fees from Astellas,

AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Novo Nordisk, MSD, Pfizer, Sanofi Aventis

in relation to treatments for diabetes and/or obesity, and has been a clinical investigator or received

institutional research support from AstraZeneca, GW Pharma, Bristol-Myers Squibb, Novo Nordisk &

Sanofi Aventis.

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SB reports having received honoraria, teaching and research sponsorship/grants from the following:

Abbott, AstraZeneca, Boehringer Ingelheim, BMS, Diartis, Eli Lilly, GlaxoSmithKline, Johnson &

Johnson, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, Schering-

Plough, Servier & Takeda.

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Abstract

The progressive nature of type 2 diabetes necessitates treatment intensification over time in order

to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin

has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control

are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as

HbA1c approaches and falls below target levels. This may account for the sub-optimal control often

achieved following insulin initiation. Combining insulin with antihyperglycaemic therapies that have

a low risk of hypoglycaemia and are weight neutral or result in weight loss is a therapeutic strategy

with the potential to improve type 2 diabetes management. Although the effects differ with each

individual class of therapy, clinical trials have demonstrated that adding a glucagon-like peptide-1

receptor agonist (GLP-1 RA), dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2

inhibitor to insulin regimens can offer a significant reduction in HbA1c without substantially

increasing hypoglycaemia risk, or weight. The evidence and merit of each approach is reviewed

within. Once-daily co-formulations of a basal insulin and a GLP-1 RA have been developed (insulin

degludec/liraglutide, IDegLira) or are under development (lixisenatide/insulin glargine, LixiLan).

IDegLira phase 3 trials and a LixiLan phase 2 trial have demonstrated robust HbA1c reductions, with

weight loss and a low risk of hypoglycaemia. With IDegLira now approved in Europe, an important

consideration will be the types of patients who may benefit most from a fixed-ratio combination:

this is discussed here, together with a look toward future developments in the field.

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1. Introduction

The pathophysiology of type 2 diabetes is complex, typically characterized by insulin resistance,

impaired insulin secretion and hyperglucagonaemia. Type 2 diabetes is also a progressive disease,

necessitating intensification of treatment over time to achieve and maintain glycaemic control.

When intensifying treatment regimens to reduce hyperglycaemia, an approach combining

treatments with complementary effects that together combat a wider spectrum of the core defects

of type 2 diabetes, would, theoretically at least, seem optimal.

Many patients ultimately require insulin therapy; insulin has unsurpassed potential efficacy but is

often underutilized due to the risk or fear of hypoglycaemia and weight gain. Landmark studies have

shown that intensive glycaemic control with insulin therapy is associated with weight gain and

severe hypoglycaemia [1–3]. Additionally, initiation and intensification of insulin therapy are often

substantially delayed. A large observational study (n = 17,374) involving 10 countries reported that

mean HbA1c at insulin initiation ranged from 67 mmol/mol (8.3%; China) up to 84 mmol/mol (9.8%;

UK), with a mean across the study of 74 mmol/mol (8.9%) [4].

The European Association for the Study of Diabetes (EASD)/American Diabetes Association (ADA)

position statement recommends an HbA1c target of <53 mmol/mol (<7.0%) with initiation of insulin

therapy, typically with basal insulin, as dual or triple therapy if a patient does not achieve/maintain

target after ~3 months of mono- or dual therapy, respectively [5]. In England and Wales, following

dual therapy, the National Institute for Health and Care Excellence (NICE) recommends treatment

intensification either with a third oral agent, a glucagon-like peptide-1 (GLP-1) agonist or basal

insulin therapy in patients with an HbA1c of ≥58 mmol/mol (≥7.5%) [6]. However, a recent

retrospective cohort study of >80,000 patients with type 2 diabetes in the UK reported that in

patients with an HbA1c ≥58 mmol/mol (≥7.5%), the median time to insulin initiation was >6 years [7].

Considering insulin intensification, another retrospective UK primary care database analysis of

patients receiving basal insulin reported that intensification of basal insulin treatment was

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uncommon (only occurred in 33% of patients), despite most patients having higher than

recommended HbA1c levels [8].

There is a clear need for earlier insulin initiation and intensification. The prospect of using new

therapies, or combination therapies, which can offer the efficacy of insulin but with an improved

risk-to-benefit profile may help to overcome this inertia. Due to the complementary nature of their

modes of action and clinical effects compared with basal insulin, GLP-1 receptor agonists (GLP-1

RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium–glucose co-transporter-2 (SGLT2)

inhibitors are increasingly being used in combination with basal insulin therapy. GLP-1 RAs improve

glycaemic control by stimulating insulin secretion and inhibiting glucagon secretion, both in a

glucose-dependent manner. Although the magnitude of clinical effects varies between different

formulations and depending on background therapy, glycaemic improvements with GLP-1 RAs are

generally accompanied by clinically significant weight loss and a low risk of hypoglycaemia. DPP-4

inhibitors have a similar mode of action to GLP-1 RAs but only increase endogenous GLP-1 levels

within the physiological range. As such, DPP-4 inhibitors offer significantly smaller HbA1c reduction

versus GLP-1 RAs and are generally weight neutral [9]. SGLT2 inhibitors are competitive inhibitors of

sodium–glucose co-transporter-2, a low-affinity, high-capacity transporter that mediates renal

glucose reabsorption [10]. Glycaemic improvements with SGLT2 inhibitors are associated with

weight loss and a low risk of hypoglycaemia [10].

The aim of this article is to review the effects of insulin initiation and intensification on glycaemic

control, also considering the incidence of hypoglycaemia and changes in body weight. We then

consider the alternative approaches to insulin intensification, such as adding a GLP-1 RA, a DPP-4

inhibitor or an SGLT2 inhibitor to basal insulin. Finally, we discuss the clinical potential of a new

approach, fixed-ratio combinations of a GLP-1 RA and a basal insulin in a single, once-daily injection.

2. Insulin initiation

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Retrospective analyses of UK primary care records indicate that initiation of insulin therapy in real-

life clinical practice results in an HbA1c reduction of 1.3–1.4% (from a baseline of 78–81 mmol/mol

[9.3–9.6%]), with less than 30% of patients achieving an HbA1c of <53 mmol/mol (<7%) [11–13].

Insulin initiation is also associated with substantial weight gain, regardless of the type of insulin

initiated (Table 1). The frequency of hypoglycaemia was not reported in these studies.

Despite the development of newer basal insulin analogues, which provide relatively peakless and

more physiological insulin-replacement therapy, neutral protamine Hagedorn (NPH) insulin is still

recommended as first-line insulin therapy in many countries, including the UK [6]. Clinical trials have

demonstrated that basal insulin analogues provide similar glycaemic improvements to NPH insulin

but with a lower incidence of hypoglycaemia and sometimes less weight gain [14–17]. Three basal

insulin analogues are available: insulin glargine (IGlar), insulin detemir (IDet) and insulin degludec

(IDeg).

Phase 3 head-to-head studies have compared basal insulin initiation in insulin-naïve patients with

type 2 diabetes of IDeg versus IGlar and IGlar versus IDet [18,19]. A similar HbA1c reduction was

reported with IDeg versus IGlar (−1.1 vs. −1.2%, respectively) and a greater HbA1c reduction with

IGlar versus IDet (−0.7 vs. −0.5%, P < 0.05) [18,19]. The overall rate of confirmed hypoglycaemia

(plasma glucose [PG] <3.1 mmol/l or severe episodes requiring assistance) was similar for IDeg

versus IGlar (1.52 vs. 1.85 events per patient-year), but the incidence of nocturnal hypoglycaemia

was significantly lower in the IDeg group versus IGlar (0.25 vs. 0.39 events per patient-year; P =

0.038) [18]. Treatment with IDet resulted in a significantly lower incidence of total hypoglycaemia

(symptomatic, major [unable to self-treat] or minor [if the patient could self-treat and PG was

confirmed <3.1 mmol/l with or without symptoms]) versus IGlar (3.29 vs. 4.41 events per patient-

year, P = 0.034), but this should be considered in the context of the lower end-of-trial HbA1c in the

IGlar group (54 mmol/mol vs. 58 mmol/mol [7.1 vs. 7.5%]) [19]. Treatment with IDeg and IGlar

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resulted in similar weight gain (2.4 vs. 2.1 kg), while IDet was weight neutral (−0.5 kg) compared

again to weight gain with IGlar (+1.0 kg) [18,19].

While the incidence of hypoglycaemia with basal insulin analogues is relatively low (compared with

more intensive insulin regimens), the risk increases substantially as HbA1c approaches and falls below

target levels (Figure 1). Data also illustrate that basal insulin analogues have a lower risk of

hypoglycaemia vs. NPH insulin at all levels of HbA1c [16,20].

It should be noted that while IDeg is approved for use in Europe, Japan and many other countries,

the FDA issued a complete response letter to IDeg, requesting additional cardiovascular safety data

from a dedicated trial [21]. As a result, the long-term safety of IDeg is being investigated in an

ongoing, 5-year cardiovascular outcomes trial in ~7,500 patients at high risk of cardiovascular

disease (DEVOTE; NCT01959529) which is expected to finish in 2016. The required number of major

adverse cardiovascular events for the pre-specified interim analysis were accumulated by the end of

January 2015 and, in April 2015, the FDA accepted for review the Class II Resubmissions for IDeg,

which included these interim data [22,23].

In summary, glycaemic improvements associated with basal insulin initiation are commonly

associated with weight gain and an increased risk of hypoglycaemia, particularly as HbA1c approaches

target levels, and to a greater extent with NPH insulin.

3. Insulin intensification

Blak et al. identified patients treated with basal insulin ± oral antidiabetic drugs (OADs) in UK primary

care (n = 3185) and evaluated treatment changes over a period of 3 years (2006–2009) [8]. Basal

insulin ± OADs was maintained without therapy intensification in 60% of patients during follow-up,

despite a mean HbA1c of 68 mmol/mol (8.4%) at baseline and 65 mmol/mol (8.1%) at end-of-trial.

During follow-up, 19% of patients were intensified with prandial (n = 464) or premixed (n = 150)

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insulin and 14% (n = 435) switched to premixed insulin. Those who were intensified with prandial or

premixed insulin had a mean baseline HbA1c of 77 mmol/mol (9.2%) and 78 mmol/mol (9.3%),

respectively, and a mean HbA1c of 70 mmol/mol (8.6%) and 72 mmol/mol (8.7%) at end of follow-up.

BMI increased by 0.3 kg/m2 with prandial intensification and by 1.1 kg/m2 with premixed

intensification. Switching from basal insulin to premixed insulin reduced mean HbA1c from 80

mmol/mol (9.5%) at baseline to 69 mmol/mol (8.5%) and was accompanied by a BMI increase of 0.9

kg/m2. The incidence of hypoglycaemia was not reported.

Phase 3 clinical trial data demonstrate the variety of options available for insulin intensification to

improve glycaemic control, but all are commonly associated with an increased risk of hypoglycaemia

and increased regimen complexity (Table 2) [24–27]. In support of the real-life data, in the clinical

trials insulin intensification was also associated with substantial weight gain.

4. Combining insulin with other agents

When insulin is initiated, metformin is usually continued as studies have shown that there is less

weight gain when the two agents are used together [28]. However, the insulin secretagogues,

sulphonylureas and glinides, may be discontinued due to an increased risk of hypoglycaemia without

additional glycaemic benefit [5]. Similarly, it is generally recommended to discontinue or reduce the

dose of thiazolidinediones (TZDs) to avoid oedema and excessive weight gain [5,29]. In contrast,

more recently available non-insulin therapies, namely GLP-1 RAs, DPP-4 inhibitors and SGLT2

inhibitors, may be continued after insulin initiation, and are also added to existing insulin therapy as

an alternative approach to insulin intensification.

4.1 Use of SGLT2 inhibitors in combination with insulin

The SGLT2 inhibitors are the newest class of oral antihyperglycaemic therapy for type 2 diabetes

management. As such, their inclusion in existing treatment algorithms is limited; however, the three

agents approved for use in Europe – dapagliflozin, canagliflozin and empagliflozin – all have broad

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licensed indications for use, including in combination with insulin [30–32]. Three phase 3 studies,

one for each agent, have compared the efficacy and safety of adding an SGLT2 inhibitor or placebo

to advanced insulin regimens (mean daily insulin doses 78–92 U) [33–35]. In all three trials, the

addition of the SGLT2 inhibitor resulted in a significant improvement in HbA1c and weight loss, but

was associated with a greater frequency of genital mycotic infections and hypoglycaemia compared

with placebo (Table 3) [33–35]. It should also be noted that in May 2015, the FDA warned that

SGLT2 inhibitors may lead to ketoacidosis [36]. Ketoacidosis does not appear to be commonly

associated with SGLT2 inhibitors, except when there are other predisposing factors present;

therefore, it is key to identify the patients most at risk and to reduce the risk to all patients [37].

Most recently, Rosenstock et al. investigated the efficacy and safety of adding the SGLT2 inhibitor

empagliflozin (10 or 25 mg) or placebo to multiple daily injections of insulin [mean 92 U/day) in

obese people (mean BMI 34.8 kg/m2) with inadequately controlled type 2 diabetes (mean HbA1c 66

mmol/mol [8.3%]) [33]. After the first 18 weeks of treatment (where total insulin dose was to remain

within 10% of prescribed dose at randomisation), the reduction in HbA1c was significantly greater

with empagliflozin 10/25 mg (−0.94/−1.02%) compared with placebo (−0.50) (P < 0.001 for both

comparisons). Body weight increased with placebo (0.34 kg) but decreased with empagliflozin

10/25 mg (−0.97/−1.54 kg) (P < 0.001 for both comparisons). The proportion of patients with

confirmed hypoglycaemia (PG ≤ 3.9 mmol/L or requiring assistance) was slightly higher in the

empagliflozin groups (40/41%) compared with placebo (37%). Consistent with previous findings,

over the full 52-week treatment period, more events consistent with genital infections were

reported by patients treated with empagliflozin 10/25 mg (4.3/9.5%) compared with placebo (1.6%).

All events were mild or moderate in intensity and only one led to discontinuation (on empagliflozin

25 mg) [33].

SGLT2 inhibitors act independently of insulin and therefore should be an effective treatment at most

stages of diabetes, and also when used in combination with insulin. SGLT2 inhibitors may also result

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in a lower risk of hypoglycaemia and weight gain when added to insulin, compared with the addition

of some other classes of drugs [5]. Based on their mechanism of action, the patients who may

experience reduced efficacy with SGLT2 inhibitors are those with renal impairment – that may also

explain the reduced efficacy with canagliflozin observed in elderly versus younger patients with type

2 diabetes [34].

4.2 Use of DPP-4 inhibitors in combination with insulin

DPP-4 inhibitors are recommended for use in combination with insulin therapy as part of the

EASD/ADA position statement [5] and five phase 3 trials have investigated the use of five different

DPP-4 inhibitors as add-on to insulin therapy. Similar to the SGLT2 inhibitor add-on studies, the DPP-

4 inhibitor or placebo were added onto a variety of insulin regimens, except in one study, which was

limited to basal insulin [38–42]. In all studies, a significantly greater reduction in HbA1c was observed

versus placebo but the HbA1c reductions were modest (−0.6 to 0.8%) considering the baseline HbA1c

(67–78 mmol/mol [8.3–9.3%]) and, as a result, mean HbA1c did not approach target levels at end-of-

trial (61–70 mmol/mol [7.7–8.6%]) (Table 3). The addition of a DPP-4 inhibitor to existing insulin

therapy was generally weight neutral (similar to addition of placebo) and hypoglycaemia was

experienced by 8–27% of patients (vs. 7–24% in placebo arms).

The addition of a DPP-4 inhibitor to insulin therapy may be of particular interest when metformin is

no longer a treatment option; for example, in patients with moderate to severe renal impairment. In

this scenario, an SGLT2 inhibitor is also contraindicated, so a DPP-4 inhibitor may be the preferred

option with a low level of treatment complexity.

4.3 Use of GLP-1 RAs in combination with basal insulin

Use of GLP-1 RAs in combination with basal insulin in triple therapy with metformin is recommended

as part of the EASD/ADA position statement: both adding basal insulin to existing metformin and

GLP-1 RA therapy or adding a GLP-1 RA to metformin and a basal insulin [5]. While this treatment

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combination has only recently been included in the product labels for some GLP-1 RAs , this is not a

new concept in secondary care in the UK [43,44]. The ABCD audits for exenatide twice daily (2007–

2009) and liraglutide (2009–2011) reported that over one third of GLP-1 RA use was in the (then)

unlicensed combination with insulin therapy [43,44].

4.3.1 Insulin initiation as add-on to a GLP-1 RA: phase 3 data

Two studies have investigated the sequential addition of the GLP-1 analogue liraglutide to OAD

therapy followed by basal insulin initiation in patients still not achieving HbA1c target (<53 mmol/mol

[<7.0%]) [45,46]. The addition of either IDet, titrated up as required (end of trial (EOT) mean dose 40

U) or IDeg (EOT mean dose 51 U) resulted in improvements in glycaemic control, to a mean end-of-

trial HbA1c of 54/48 mmol/mol (7.1/6.5%), with a very low risk of hypoglycaemia (Table 3). The

addition of IDet resulted in maintenance of liraglutide-associated weight loss during the run-in

period, while insulin initiation with IDeg resulted in weight gain of 2.0 kg.

These data suggest that continuing with existing GLP-1 RA therapy is beneficial when initiating

insulin therapy, with the potential to lower HbA1c to below target levels with a very low risk of

hypoglycaemia.

4.3.2 Insulin intensification with the addition of a GLP-1 RA: phase 3 data

The GLP-1 RAs as a class can broadly be divided into two categories: short- and long-acting. Short-

acting GLP-1 RAs (exenatide twice daily and lixisenatide) target postprandial glucose at the meal

immediately after dosing, an effect predominantly due to a delay in gastric emptying [47,48]. Long-

acting GLP-1 RAs (liraglutide and weekly GLP-1 RAs) target both fasting plasma glucose (FPG) and

postprandial glucose across all three daily meals, due to their 24-hour action profiles. However, their

impact on postprandial glucose at the meal after dosing is significantly lower compared with short-

acting GLP-1 RAs, but often greater with long-acting GLP-1 RAs at subsequent meals when the short-

acting GLP-1 RA is not dosed again [48–50].

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Seven phase 3 studies have investigated the addition of a GLP-1 RA in patients uncontrolled on basal

insulin therapy (Table 3) [51–57]. In four studies, the addition of the GLP-1 RA was compared with

placebo while three studies compared the addition of a GLP-1 RA to basal insulin intensification with

one or three daily bolus insulin doses.

The addition of a GLP-1 RA to basal insulin resulted in a significantly greater reduction in HbA1c

versus the addition of placebo, and a significant reduction from baseline in body weight in three of

the four studies (Table 3). Although the patient populations and background insulin titration varied

across the studies, a crude comparison suggests that the long-acting GLP-1 RA liraglutide (placebo-

corrected change in HbA1c −1.2%) resulted in a greater reduction in HbA1c when added to basal

insulin compared to short-acting GLP-1 RAs (placebo corrected change in HbA1c −0.4 to −0.7%).

Mathieu et al. compared the addition of liraglutide 1.8 mg versus IAsp (before the largest meal) in

patients uncontrolled (HbA1c ≥53 mmol/mol [≥7.0%]) on IDeg and metformin [54]. After 26 weeks,

the addition of liraglutide resulted in a significantly greater reduction in HbA1c versus IAsp (−0.74 vs.

−0.39%; P = 0.0024). Liraglutide addition was associated with weight loss, while IAsp resulted in

weight gain (−2.8 vs. +0.9 kg; P < 0.0001). The observed rate of confirmed hypoglycaemia was over

8-fold greater with IAsp versus liraglutide (8.15 vs. 1.00 episodes per patient-year; P < 0.0001), while

gastrointestinal adverse events were more common with liraglutide, with 1.1% of patients in the

liraglutide group withdrawing due to nausea or vomiting. Rosenstock et al. compared the addition of

another long-acting GLP-1 RA, albiglutide 30 mg once weekly (OW), versus three-times daily (TID)

insulin lispro (ILisp) to IGlar and metformin and/or pioglitazone [55]. After 26 weeks of treatment,

there was a significantly greater reduction in HbA1c with albiglutide OW versus ILisp TID (−0.82 vs.

−0.66%; P < 0.0001). Weight decreased with albiglutide but increased with ILisp (−0.73 vs. +0.81; P <

0.0001). More patients experienced documented hypoglycaemia with ILisp versus albiglutide (30%

vs.16%) and gastrointestinal adverse events with albiglutide versus ILisp (nausea: 11% vs. 1%).

Finally, Diamant et al. compared the addition of the twice-daily short-acting GLP-1 RA exenatide

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versus ILisp TID to patients uncontrolled on IGlar [57]. Unlike the long-acting GLP-1 RAs that

provided a superior HbA1c reduction versus the additional of mealtime insulin, addition of exenatide

twice daily (BID) resulted in a similar HbA1c reduction (−1.13% vs. −1.10%) to ILisp TID, while again

weight decreased with the GLP-1 RA and increased with insulin intensification (exenatide BID: −2.5

kg; ILisp TID: +2.1 kg; P < 0.001). The incidence of minor hypoglycaemia was significantly greater with

ILisp (41% vs. 30%; P = 0.004), while more patients experienced gastrointestinal adverse events with

exenatide (47% vs. 13%), with 3.5% of patients in the exenatide group withdrawing due to nausea or

vomiting.

In summary, several phase 3 clinical trials have now shown that combining a GLP-1 RA with basal

insulin results in a significant HbA1c reduction, in some cases to well within target levels, while

maintaining a low risk of hypoglycaemia and often with the added benefit of weight loss (Table 3)

[45,46,51–56]. In general, long-acting GLP-1 RAs appear to be the most potent at lowering HbA1c and

may be the best choice for patients who are not near their HbA1c target after basal optimisation.

Short-acting GLP-1 RAs may be an alternative in patients already near target and experiencing

significant postprandial glucose excursions [58–60]. The studies involving liraglutide, albiglutide and

exenatide BID have shown that GLP-1 RAs are a particularly attractive alternative to intensification

with mealtime insulin dose(s) [54,55,57].

As a result of the benefits of co-usage of a GLP-1 RA and basal insulin demonstrated in ‘loose

combination’ studies, a product combining the complementary clinical effects of liraglutide and IDeg

(IDegLira) in a single, once-daily injection has been developed. Additionally, a product combining

lixisenatide and insulin glargine (LixiLan) in a single injection is under development.

5. IDegLira, a novel once-daily combination of a basal insulin and GLP-1 RA

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IDegLira is the only fixed-ratio combination of a basal insulin (IDeg) and a GLP-1 RA (Lira), delivered

once daily in one pen, currently approved for use in Europe [61]. The dose ratio is such that one dose

step of IDegLira is the equivalent of 1 U of IDeg and 0.036 mg of Lira (maximum dose: 50 U IDeg/1.8

mg Lira). The starting dose of IDegLira in phase 3 trials has been 10 dose steps (10 U IDeg/0.36 mg

liraglutide) in patients uncontrolled on OADs, ensuring insulin dose equivalent to a recommended 10

U initiation of basal insulin, and 16 dose steps (16 U IDeg/0.58 mg liraglutide) in patients previously

uncontrolled on basal insulin or a GLP-1 RA, ensuring the highest possible insulin dose in those

transferring from pre-trial basal insulin, while taking into consideration the recommended starting

dose of liraglutide (0.6 mg). In clinical trials, titration was performed in a similar manner to basal

insulin titration, twice weekly based on self-measured FPG target of 4.0–5.0 mmol/L with dose

changes of +2/−2 dose steps if patients were above or below the FPG target, respectively. The two

phase 3 trials, DUAL I and DUAL, II were included as part of the submission package for review by

European Medicines Agency: DUAL I (IDegLira vs. IDeg or Lira in patients uncontrolled on OADs; 26

weeks with 26-week extension) and DUAL II (IDegLira vs. IDeg in patients uncontrolled on basal

insulin + OADs; 26 weeks) [62,63].

5.1 IDegLira compared with its individual components, IDeg or liraglutide alone, in patients

uncontrolled on oral glucose-lowering therapy (DUAL I)

In a randomized, open-label study in 1663 patients with T2D uncontrolled (HbA1c 53–86 mmol/mol

[7.0–10.0%]) on metformin ± pioglitazone, IDegLira (n=834) was compared with IDeg (n=414) or

liraglutide (n=415) alone. Liraglutide was titrated by 0.6 mg/week to a maintenance dose of 1.8 mg

[62]. IDegLira could be titrated to a maximum of 50 dose steps (50 units IDeg/1.8 mg liraglutide); no

maximum dose was specified for the IDeg arm. At screening, >80% of patients were receiving

metformin monotherapy and at baseline, mean HbA1c was 67 mmol/mol (8.3%), mean BMI was

31.2–31.3 kg/m2 and mean duration of diabetes was ~7 years.

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Treatment with IDegLira resulted in a significantly greater reduction in HbA1c and a greater

proportion of subjects achieving HbA1c targets of <53 mmol/mol (<7.0%) (81% vs. 65%/60%) and ≤48

mmol/mol (≤6.5%) (70% vs. 47%/41%) versus IDeg or liraglutide alone (Table 4).

The liraglutide component of IDegLira appeared to mitigate insulin-associated weight gain and the

rate of confirmed hypoglycaemia was 32% lower with IDegLira versus IDeg (P = 0.0023), but higher

versus liraglutide (P < 0.0001), which had a very low rate of hypoglycaemia (Table 4). Compared with

IDeg alone, IDegLira was associated with a significantly lower insulin dose (Table 4). Numerically

fewer patients experienced gastrointestinal adverse events with IDegLira versus liraglutide, likely

due to the slower up-titration of the liraglutide component in IDegLira and the lower mean end-of-

trial dose (Table 4).

In a 26-week extension study, the 26-week HbA1c of 6.4% observed with IDegLira was maintained to

week 52 with only a mean dose increase of one dose step (1 U IDeg/0.036 mg liraglutide) to 39 dose

steps, demonstrating the durability of treatment effects (Table 4) [64].

5.2 IDegLira versus IDeg in patients with type 2 diabetes poorly controlled on basal insulin (DUAL II)

DUAL II was a 26-week trial designed to assess the relative contribution of the liraglutide component

of IDegLira by comparing it with IDeg, with a dose cap of 50 U. Unlike DUAL I, which was an open-

label study, DUAL II was double-blinded. The trial included patients with type 2 diabetes

uncontrolled on basal insulin (20–40 units) and metformin ± sulphonylurea/glinides (SU/glinide

discontinued at baseline) [63].

After 26 weeks of treatment, the mean insulin dose was equivalent for both IDegLira and IDeg,

allowing evaluation of the contribution of the liraglutide component of IDegLira (Table 4). HbA1c

reduction was 1.1% greater with IDegLira compared with IDeg (P < 0.0001) (Table 4), with a greater

proportion of patients achieving an HbA1c target of <53 mmol/mol (<7.0%) with IDegLira versus IDeg

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(60% vs. 23%; P < 0.0001). IDegLira resulted in weight loss of 2.7 kg compared with no weight change

in the IDeg group (P < 0.0001). Rates of confirmed hypoglycaemia were similar with IDegLira and

IDeg, despite the lower end-of-trial HbA1c in the IDegLira arm (Table 4). Overall, the frequency of

adverse events was similar, with very low and comparable rates of nausea in this double-blinded

trial.

These data illustrate that in patients with type 2 diabetes uncontrolled on basal insulin, the addition

of the liraglutide component in IDegLira offers superior glycaemic control to IDeg at equivalent

insulin doses, without a higher risk of hypoglycaemia and with the additional benefit of weight loss.

5.3 IDegLira: which patients may benefit most?

As a new treatment option for patients with type 2 diabetes, it is important to consider which

patients may benefit most from a fixed-ratio combination of a GLP-1 RA and basal insulin such as

IDegLira.

Based on the summary of product characteristics, IDegLira is licensed for use with oral glucose-

lowering medicinal products when these alone or combined with basal insulin do not provide

adequate glycaemic control [61]. Considering that GLP-1 RAs and basal insulin are already available

for use in ‘free’ or ‘loose’ combination, IDegLira may be considered in patients who are very poorly

controlled (HbA1c >8.5%) on oral therapy, where initiation of a GLP-1 RA or basal insulin alone may

not be sufficient, and initiation of basal–bolus or premix insulin is not appropriate. Another group of

patients who may be considered for IDegLira are those with significant weight problems who are

already receiving modest doses of basal insulin and failing to achieve their glycaemic targets – the

convenience of IDegLira compared with the addition of a second injection when adding a GLP-1 RA

may appeal to some patients; other options might include insulin intensification, with known risks of

weight gain and hypoglycaemia, or the addition of an SGLT2 inhibitor or DPP-4 inhibitor. Although

not currently licensed or studied to date, given the improved gastrointestinal tolerability of IDegLira

16

versus a GLP-1 RA, patients who have previously been unable to tolerate standard GLP-1 RA up-

titration may find a fixed-ratio preparation more acceptable.

5.4 Fixed-ratio combinations: what’s next?

Additional clinical trial data for IDegLira are expected in 2015, which will describe the safety and

efficacy of IDegLira when added to existing SU ± metformin therapy (DUAL IV), when switching from

a GLP-1 RA (DUAL III) and in patients uncontrolled on basal insulin therapy versus up-titration of

insulin glargine (DUAL V). In addition, there is another fixed-ratio combination of a GLP-1 RA and

basal insulin under development. The LixiLan device combines lixisenatide and insulin glargine in one

pen with a maximum dose of 60 U insulin glargine and 30 µg lixisenatide used in a phase 2 study

[65]. The study compared the safety and efficacy of adding LixiLan or insulin glargine in patients

uncontrolled on metformin. After 24 weeks, mean HbA1c had decreased from 8.0% at baseline to

6.3% and 6.5% with LixiLan and insulin glargine, respectively (treatment difference −0.17%, P = 0.01).

LixiLan resulted in a weight reduction of 1 kg while weight increased by 0.5 kg with insulin glargine

(treatment difference −1.4 kg, P < 0.0001), with a similar proportion of patients experiencing

hypoglycaemia in both arms (22 vs. 23%). Two LixiLan phase 3 studies were initiated in 2014 and

results are expected late in 2015.

6. Summary

Insulin initiation and intensification are often severely delayed. The initiation of insulin therapy is

associated with weight gain and hypoglycaemia, particularly as patients approach target HbA1c

levels. Intensification of insulin therapy to improve glycaemic control often results in further weight

gain and an increased risk of hypoglycaemia. Use of an SGLT2 inhibitor, DPP-4 inhibitor or GLP-1 RA

in combination with basal insulin can reduce these insulin-associated side effects. While GLP-1 RAs

have largely been studied in combination with basal insulin, SGLT2 inhibitors (and to a lesser extent

17

DPP-4 inhibitors) have been shown to be effective at reducing HbA1c and body weight when added to

advanced insulin regimens.

Combining both a GLP-1 RA and basal insulin in a once-daily injection using a simple pen device may

help overcome clinical inertia to treatment intensification caused by hypoglycaemia, weight gain,

treatment complexity or the inability to use a GLP-1 RA due to gastrointestinal side effects.

Additional data from the IDegLira and LixiLan clinical programmes are now awaited to further

establish the safety and efficacy of fixed-ratio combinations in additional patient populations with

type 2 diabetes.

Acknowledgements

All authors have contributed to the design, structure and content of this manuscript. The authors

thank David Harvey and Daria Renshaw at Watermeadow Medical for medical writing and editorial

assistance (funded by Novo Nordisk). The authors did not receive payment in relation to the

preparation of this article.

18

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25

Tables and figures

Table 1 Insulin initiation in UK clinical practice [11–13]

Data source

N Duration Type of insulin initiated

Baseline HbA1c

Change in HbA1c

End-of-study HbA1c

Patients achieving HbA1c target(s)

Change in body weight

Practice records [11]

516 3 years Basal 78.1 mmol/mol (9.3%)

−15.3 mmol/mol(−1.4%) at 6 months, similar at 3 years*

63 mmol/mol (7.9%) at 6 months, similar at 3 years*

HbA1c <53 mmol/mol (<7%): 29%*

+3.6 kg*

GPRD [12]

3783 2 years Basal (41%)NPH (29%)Premix (29%)Short acting (5%)

81.4 mmol/mol (9.6%)

−15.3 mmol/mol(−1.4%)

66 mmol/mol (8.2%)†

HbA1c ≤58 mmol/mol (≤7.5%):26–41%, depending on baseline BMI

After 1 year:Basal, +3.4 kgNPH, +3.7 kgPremix, +4.4 kgShort acting, +3.5 kg

THIN [13] 4045 6 months Basal (52%)Premix (42%)Basal–bolus (4%)Prandial (2%)

81.4 mmol/mol (9.6%)

−14.2 mmol/mol −1.3%

67 mmol/mol (8.3%)

HbA1c <53 mmol/mol (<7%):17%HbA1c <58 mmol/mol (<7.5%): 30%

+0.9 kg (25% of patients gained >3.6 kg)

*At end-of-study, 43% of patients had intensified their basal insulin by incorporating short-acting insulins. †Not reported in publication, calculated by mean baseline value minus mean change.

BMI, body mass index; NPH, neutral protamine Hagedorn

26

Table 2 Landmark clinical trials studying the effects of insulin intensification [24–27]

Study Duration Background treatment

Randomized treatment added Baseline HbA1c

Change in HbA1c

End-of-trial HbA1c

Hypoglycaemia(events/patient/year)

Weight change

Holman et al. 2009 (4-T) [24]

3 years

MET + SU BIAsp 70/30 BID(+ midday IAsp)

70 mmol/mol (8.6%) −1.3% 54 mmol/mol

(7.1%) 3.0 +5.7 kg

MET + SU IDet OD (+ IAsp TID) 68 mmol/mol (8.4%) −1.2% 52 mmol/mol

(6.9%) 1.7 +3.6 kg

MET + SU IAsp TID (+ IDet OD) 70 mmol/mol (8.6%) −1.4% 51 mmol/mol

(6.8%) 5.7 +6.4 kg

Lankisch et al. 2008 (OPAL) [25]

24 weeksIGlar + OADs IGlu breakfast 57 mmol/mol

(7.4%) −0.3% 53 mmol/mol (7.0%) Overall: 2.72 +1.0 kg

IGlar + OADs IGlu main meal 56 mmol/mol (7.3%) −0.4% 52 mmol/mol

(6.9%) Overall: 3.69 +0.9 kg

Meneghini et al. 2011 (STEPwise) [27]

12 + 3x12 weeks

IDet + OADsStepwise addition of IAsp doses to largest perceived

meal

72 mmol/mol (8.7%) −1.1%

58 mmol/mol (7.5%) Minor: 6.0

Major: 0.04 +2.7 kg

IDet + OADsStepwise addition of IAsp dose to meal with largest

PPG increment

74 mmol/mol (8.9%) −1.3%

61 mmol/mol (7.7%) Minor: 5.9

Major: 0.01 +2.0 kg

Davidson et al. 2011 [26] 24 weeks

IGlar + OADs 1 x IGlu 63 mmol/mol (7.9%) −0.4% 57 mmol/mol

(7.4%) Severe: 0.28 +3.8 kg

IGlar + OADs 2 x IGlu 62 mmol/mol (7.8%) −0.4% 57 mmol/mol

(7.4%) Severe: 0.89 +4.1 kg

IGlar + OADs 3 x IGlu 62 mmol/mol (7.8%) −0.4% 56 mmol/mol

(7.3%) Severe: 0.64 +3.9 kg

BIAsp, biphasic insulin aspart; BID, twice daily; IAsp, insulin aspart; IDet, insulin detemir; IGlar, insulin glargine; IGlu, insulin glulisine; MET, metformin; OAD, oral antidiabetic drug; OD, once daily; PPG, postprandial glucose; SU, sulphonylurea; TID, three-times daily.

27

Table 3 Phase 3 studies assessing the combination of SGLT2 inhibitors, DPP-4 inhibitor and GLP-1 RAs with insulin therapy [33–35,38–42,45,56,51–57]

Reference Treatment arm(not including background OADs or comparator arms)

Baseline insulin dose (U/day)

Permitted insulin dose changes/titration

Change in insulin dose

(U/day)

Baseline HbA1c

Change in HbA1c

Placebo corrected

HbA1c

End-of-trial

HbA1c

Change in body weight

Addi

tion

of a

n SG

LT2

inhi

bito

r to

insu

lin

Neal et al. 2015≠ [34]

Insulin + canagliflozin 300 mg 60

Stable background insulin dose (maintained within

15% of randomisation dose)NR

67 mmol/mol

(8.3%)NR −0.73 NR −2.4%

Wilding et al. 2012 [35]

Insulin + dapagliflozin 10 mg 78

Stable background insulin dose (maintained within

10% of randomisation dose)

−0.7 (+10.5 with

placebo)

70 mmol/mol

(8.6%)−0.96 −0.57

60 mmol/m

ol (7.6%)**

−1.61 kg

Rosenstock et al. 2014≠ [33]

MDI insulin + empagliflozin 25 mg 92

Stable background insulin dose (maintained within

10% of randomisation dose)NR

67 mmol/mol

(8.3%)−1.02 −0.52

56 mmol/mol (7.3%)

−1.54 kg

Addi

tion

of a

DP

P-4

inhi

bito

r to

insu

lin

Rosenstock et al. 2009 [38] Insulin + alogliptin 25 mg 55

Continued pre-randomisation insulin dose +0.4 (+0.6

with placebo)

78 mmol/mol

(9.3%)−0.7 −0.6

70 mmol/m

ol (8.6%)**

+0.6 kg

Vilsbøll et al. 2010 [39] Insulin + sitagliptin 100 mg 67/44†

Stable background insulin dose

0 (+1.6 with

placebo)

72 mmol/mol

(8.7%)−0.6 −0.6

65 mmol/mol (8.1%)

+0.1 kg

Barnett et al. 2012 [40] Insulin + saxagliptin 5 mg 53

Stable background insulin dose (maintained within

20% of randomisation dose)

+1.7 (+5.0 with

placebo)

72 mmol/mol

(8.7%)−0.7 −0.4

64 mmol/m

ol (8.0%)**

+0.4 kg

Yki-Järvinen et al. 2013 [41]

Basal insulin + linagliptin 5 mg 42

Stable background insulin dose (maintained within

10% of randomisation dose)

+0.1 (+0.4 with

placebo)

67 mmol/mol

(8.3%)−0.6 −0.65

61 mmol/mol (7.7%)

−0.2 kg

Kothny et al. 2013 [42] Insulin + vildagliptin 50 mg 40

Stable background insulin dose (maintained within

10% of randomisation dose)

−1.1 (−0.2 with

placebo)

73 mmol/mol

(8.8%)−0.8 −0.7

64 mmol/m

ol (8.0%)**

+0.1 kg

28

GLP-

1 RA

in c

ombi

natio

n w

ith b

asal

insu

linAddition of basal insulin to a GLP-1RA

DeVries et al. 2012 [45] Liraglutide 1.8 mg + IDet 0

IDet started at 10 U and then titrated weekly to FPG

4.1-6.0 mmol/L+39.5

60 mmol/mol

(7.6%)−0.5 N/A

54 mmol/mol (7.1%)

−0.2 kg

Aroda et al. 2014 [46] Liraglutide 1.8 mg + IDeg

0 IDeg started at 10 U and then titrated to FPG 4-5

mmol/L+51

58 mmol/mol

(7.5%)−1.04 −0.92

48 mmol/mol (6.5%)

+2.0 kg

Addition of a GLP-1RA to basal insulin vs. placebo

Buse et al. 2011 [51] IGlar + exenatide 10 µg BID 50Background IGlar titrated to

<5.6 mmol/L+13 (+20

with placebo)

67 mmol/mol

(8.3%)−1.74 −0.69

49 mmol/mol (6.6%)

−1.8 kg

Riddle et al. 2013 [52] IGlar + lixisenatide 20 µg 43

Background IGlar titrated to 4.4-5.6 mmol/L

+3.1 (+5.3 with

placebo)

60 mmol/mol

(7.6%)−0.71 −0.32

53 mmol/mol (7.0%)

−1.8 kg

Riddle et al. 2013 [53]

Basal insulin + lixisenatide 20 µg 54

Basal insulin dose reduced 20% at baseline if HbA1c

≤7.5%. Insulin dose maintained within 20% of

randomisation dose

−5.6 (−1.9 with

placebo)

68 mmol/mol

(8.4%)−0.7 −0.4

62 mmol/mol (7.8%)

+1.2 kg

Ahmann et al. 2014 [56]

Basal insulin + liraglutide 1.8 mg 48#

Basal insulin dose reduced 20% at baseline if HbA1c

≤8.0%. Insulin dose maintained at pre-trial level.

−5 (−1 with

placebo)

66 mmol/mol

(8.2%)−1.30 −1.2

52 mmol/mol (6.9%)

−3.5 kg

Addition of a GLP-1RA to basal insulin vs. meal-time insulin

Mathieu et al. 2014 [54]

IDeg + liraglutide 1.8 mg 69#IDeg dose decreased by 20% at baseline and up-titrated if FPG ≥5 mmol/L after week 6

−761

mmol/mol (7.7%)

−0.74 N/A53

mmol/mol (7.0%)

−2.8 kg

Rosenstock et al. 2014 [55]

IGlar + albiglutide 30 mg OW 47

IGlar titrated to <5.6 mmol/L +6

69 mmol/mol

(8.5%)−0.82 N/A

60 mmol/mol (7.6%)

−0.73 kg

Diamant et al. 2014 [57]

IGlar + exenatide 10 µg BID 61Background IGlar reduced

by 10% at baseline and then titrated to ≤5.6 mmol/L

−4.567

mmol/mol (8.3%)

−1.13 N/A55

mmol/mol (7.2%)

−2.5 kg

29

≠18-week efficacy data are presented before insulin titration was permitted in the study. *Placebo-corrected value; **Not reported, calculated using baseline value and change in HbA1c value reported; † 67 U for those on premixed insulin (27%) and 44 U for those on long- or intermediate-acting insulin (73%); # Basal insulin dose reduced by 20% at randomization

BID, twice daily; DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IDeg, insulin degludec; IDet, insulin detemir; IGlar, insulin glargine; MDI, multiple daily injections; NR, not reported; OAD, oral antidiabetic drug; OW, once weekly; SGLT2, sodium–glucose co-transporter-2

30

Table 4 Summary of key data from the IDegLira phase 3a clinical trials [62–64]

Study Study duration

Treatment arms

Mean EOT dose

Mean ΔHbA1c

(%)

Mean EOT HbA1c (%)

Hypoglycaemia (events/

patient-year)

Mean Δ body

weight (kg)

DUAL I(Gough et al. 2014) [62]

26 weeks

IDegLira 38 dose steps (38 U; 1.4 mg) −1.9*,† 6.4 1.8*,† −0.5*,†

IDeg 53 U −1.4 6.9 2.6 +1.6

Lira 1.8 mg 1.8 mg −1.3 7.0 0.2 −3.0

DUAL I extension(Gough et al. 2014) [64]

52 weeks

IDegLira 39 dose steps (39 U; 1.4 mg) −1.8*,† 6.4 1.8*,† -0.4*,†

IDeg 62 U −1.4 6.9 2.8 +2.3

Lira 1.8 mg 1.8 mg −1.2 7.1 0.2 −3.0

DUAL II(Buse et al. 2014) [63]

26 weeksIDegLira 45 dose steps

(45 U; 1.6 mg) ½1.9* 6.9 1.5 −2.7*

IDeg (max 50 U) 45 U −0.9 8.0 2.6 0.0

*P < 0.0001 vs. IDeg; †P < 0.0001 vs. liraglutide

EOT, end-of-trial; IDeg, insulin degludec; IDegLira, insulin degludec/liraglutide

31

Figure 1 Relationship between incidence of hypoglycaemia (events per patient-year) and end-of-study HbA1c [16,20]

A. IDet vs. NPH as add-on to OAD therapy in insulin-naïve patients with T2D in a 26-week study [16]. (Adapted from Hermansen et al. Diabetes Care 2006, with permission from Elsevier.)

B. IGlar vs. NPH in combination with OAD therapy in patients with T2D in a 5-year study. Prandial insulin could be added at the investigator’s discretion [20]. (Adapted from Rosenstock et al. J Diabetes Complications, with permission from the American Diabetes Association.)

IDet, insulin detemir; IGlar, insulin glargine; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug; T2D, type 2 diabetes

32